New Drug Dawns In Cancer Treatment

October 17, 1999|By John Crewdson Chicago Tribune

BOSTON - It's show time, and Moses Judah Folkman admits he is nervous.

Three decades after the Harvard University surgeon began proselytizing a radical new approach to cancer treatment, three years after his laboratory discovered a naturally occurring protein that fulfilled his hypothesis by permanently obliterating tumors in mice, the first human trial of the drug known as endostatin is beginning at last - and with it, a new era in cancer treatment.

Early this week, three patients selected at random will be attached to intravenous lines. During the next hour, their bodies will be infused with a colorless solution containing a few milligrams of endostatin.

The patients, whose identities are being kept confidential, will repeat the routine each morning for the next 28 days, while physicians monitor them for side effects and study their tumors and blood for evidence that endostatin might be impairing the growth of blood vessels those tumors need to flourish.

Without the flow of fresh blood to deliver oxygen and nutrients and remove waste products, tumor cells, like other cells, wither and die.

Most of the tumors Folkman has cured in mice resemble mouse-sized knapsacks, the equivalent of a four- or five-pound cancer in an adult human. The tumors being treated here will not be nearly that large.

David Nathan, who heads the Dana-Farber Cancer Institute here, headquarters for the trial, predicts that if endostatin is active in people, ``there may be rare patients who will respond. The problem is, when patients have remissions in very small trials, you really don't know why they've had a remission.''

Folkman has always been the first to emphasize that a stunning success in mice does not necessarily equal even a qualified success in man. As he awaits the onset of the endostatin trial, he ponders the cautionary experience of a major pharmaceutical company that recently tested a drug thought to block a key cancer gene.

``In mice [the gene-blocking drug) regresses tumors very fast,'' Folkman says. ``Then they go into the clinic, and it's been tough. They've had deaths, it hasn't worked, there've been side effects.''

However, no side effects have been seen in mice or monkeys from endostatin, even at extremely high doses. But Folkman is well aware that endostatin could fail for reasons he cannot foresee, that in patients it might behave ``just like water - that it would have no effect, and tumors would grow merrily on. It might fail for a million reasons. Most drugs fail.''

Such pitfalls aside, the deck is already stacked against endostatin, as it is against any prospective cancer treatment. For ethical reasons, new drugs must be tested first on patients in whom all other treatments have failed, which means patients whose tumors are already large and growing fast.

And, because the endostatin study is a ``Phase I'' clinical trial, the first patients will receive a low dose, increasing to a maximum of 16 times that amount in successive groups of patients throughout the fall and winter. But researchers agree that expecting a small dose of a new drug to help a severely ill patient in a short period is asking a great deal.

``We're seeing all the people saying, `Well, it won't work because you can't treat slow-growing tumors,''' Folkman says. ```And you can't get small early tumors, because the patients who are allowed to go to clinical trials are near death.' Or, ` ... because the right course is nine months, and nobody is going to be kept on for nine months.'''

Folkman, who has spent half his life convincing other scientists that tumors can be eviscerated by cutting off their blood supply, will not be surprised if endostatin shows early benefits.

What concerns him is should endostatin fail initially, there might be no future trials.